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Journal of Virology, August 2005, p. 9492-9502, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9492-9502.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Frequent Coinfection of Cells Explains Functional In Vivo Complementation between Cytomegalovirus Variants in the Multiply Infected Host

Luka Cicin-Sain,1,{dagger} Jürgen Podlech,2 Martin Messerle,3 Matthias J. Reddehase,2 and Ulrich H. Koszinowski1*

Max von Pettenkofer Institute, Ludwig Maximilians-University, Munich, Germany,1 Institute for Virology, Johannes Gutenberg-University, Mainz, Germany,2 Virus Cell Interaction Group, Medical Faculty, University of Halle-Wittenberg, Halle (Saale), Germany3

Received 14 January 2005/ Accepted 19 April 2005

In contrast to many other virus infections, primary cytomegalovirus (CMV) infection does not fully protect against reinfection. Accordingly, clinical data have revealed a coexistence of multiple human CMV variants/strains in individual patients. Notably, the phenomenon of multiple infection was found to correlate with increased virus load and severity of CMV disease. Although of obvious medical relevance, the mechanism underlying this correlation is unknown. A weak immune response in an individual could be responsible for a more severe disease and for multiple infections. Alternatively, synergistic contributions of variants that differ in their biological properties can lead to qualitative changes in viral fitness by direct interactions such as genetic recombination or functional complementation within coinfected host cells. We have addressed this important question paradigmatically with the murine model by differently designed combinations of two viruses employed for experimental coinfection of mice. Specifically, a murine cytomegalovirus (MCMV) mutant expressing Cre recombinase was combined for coinfection with a mutant carrying Cre-inducible green fluorescent protein gene, and attenuated mutants were combined for coinfection with wild-type virus followed by two-color in situ hybridization studies visualizing the replication of the two viruses in infected host organs. These different approaches concurred in the conclusion that coinfection of host cells is more frequent than statistically predicted and that this coinfection alters virus fitness by functional trans-complementation rather than by genetic recombination. The reported findings make a major contribution to our molecular understanding of enhanced CMV pathogenicity in the multiply infected host.

* Corresponding author. Mailing address: Max von Pettenkofer-Institut, Pettenkoferstrasse 9a, 80336 Munich, Germany. Phone: 49-89-5160-5290. Fax: 49-89-5160-5292. E-mail: koszinowski{at}mvp.uni-muenchen.de.

{dagger} Present address: Vaccine and Gene Therapy Institute, Oregon Health & Science University, OHSU West Campus, 505 NW 185th Ave., Beaverton, OR 97006.

Journal of Virology, August 2005, p. 9492-9502, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9492-9502.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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